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Inflammatory Bowel Disease (IBD)

What is Inflammatory Bowel Disease (IBD)?

Inflammatory bowel disease (IBD) is a chronic inflammatory condition comprised of two major disorders: ulcerative colitis (UC) and Crohn disease (CD). These disorders have distinct yet overlapping pathologic and clinical characteristics; however, their pathogenesis remains poorly understood.
Prevalence and Incidence

Today, CD prevalence is roughly equivalent to that of UC in both North America and Europe. One of the largest North American studies, based on health insurance data from 9 million subjects, calculated CD prevalence to be 201 and UC prevalence to be 238, estimating more than 1.3 million adults with IBD in the United States2.

IBD incidence appears to be lower in South America, Asia, and the Middle East (see Figure 1)3,4; however, there appears to be a steady rise in incidence of IBD during the last few decades, highest among adolescents and young adults with peak onset of 15-35 years of age13. Women, in general, have a 20-30% higher risk of developing CD, though no such gender difference is observed for UC.
Disease Course The disease course in UC can be described in terms of disease activity, number of relapses, surgical history, and mortality. With treatment, the course of UC typically consists of intermittent exacerbations that alternate with long periods of remission. Inflammation is limited to the mucosal layer of the colon and may commonly involve the rectum. Approximately 67 percent of patients experience at least one relapse within 10 years of diagnosis. Approximately 20 to 30 percent of patients will require colectomy for acute complications or for medically intractable disease14. Long-term complications of UC include strictures, dysplasia, and colorectal cancer. The risk of colorectal cancer appears to be highest in patients with pancolitis, with risk being shown to increase 8 to 10 years into diagnosis15. Overall mortality appears to be highest in the first year after ulcerative colitis diagnosis, though these rates have decreased over time16.

In CD, inflammation is characterized as transmural and can affect any portion of the gastrointestinal tract from the mouth to the perianal area, which leads to a spectrum of clinical manifestations more variable than that of UC. Although anatomical distribution is fairly stable over time, the behavior of the disease may vary significantly with passing time. For example, a French study17 looking at various CD phenotypes found nonstricturing or nonpenetrating types in 70% of patients, stricturing in 17%, and penetrating in 13%. At 10 year follow-up, 27% and 30% of nonstricturing types had transformed to stricturing and  penetrating disease, respectively. Approximately 10-30% of CD patients experience relapse or disease exacerbation after the first year of diagnosis. At 10-15 years following, 13% will have a relapse free course, 20% will have annual relapses, and 67% will have a chronic intermittent course18. Most patients with CD ultimately require surgery, with risk for hemicolectomy at approximately 35% after 10 years from diagnosis19.  Recurrence of perianal fistulas after medical or surgical therapy is common. Given disease heterogeneity, overall life expectancy in patients with CD is not well established.
Clinical Manifestations Table 1 provides a comprehensive list of the most common clinical, biochemical, and pathological features distinguishing UC from CD5.The systemic nature of IBD disease is an important consideration for both UC and CD patients. Extra-intestinal manifestations associated with IBD are identifiable in approximately 10 percent of patients at presentation and up to 30 percent of patients within the first few years following diagnosis29. These manifestations tend to occur more commonly with colonic involvement.

Inflammatory arthropathies are the most common extra-intestinal manifestations in IBD patients with prevalence between 7-25%. Other common complications include hepatobiliary disease; cutaneous manifestations which can include granulomatous perianal/peristomal ulcers or fistulas, reactive erythema nodosum or pyoderma gangrenosom, acrodermatitis enteropathica secondary to nutritional deficiency (namely, zinc); ocular manifestations such as anterior uveitis, cataracts, or glaucoma (due to drug exposure); increased risk of osteoporosis, osteopenia, thromboembolism, and anemia; and nephrolithiasis, among many others28. Therefore, IBD not only affects bowel but practically every other organ via various mechanisms. Treatment of underlying disease becomes essential here, in addition to adequate treatment of all additional manifestations to maintain patient health and quality of life.
Effect on Female Fertility

Women with inactive IBD appear to have fertility equivalent to the general population9. A recent study investigating ovarian reserve status in woman with CD by serum AMH levels found that subjects did not have severe ovarian reserve alterations compared with the control population21. Reasons for low birth rates among these women are likely secondary to psychological factors and/or are treatment-related. As an example, voluntary “childlessness” and patient self-overestimation of IBD-related reproductive risks has been reported as one cause for reduced fertility rates among IBD patients. Concerns about fertility seemed highest among women with CD and a history of disease-related surgery20. While IBD itself has not been found to impact fertility, it is the active inflammation, medications, and/or surgeries associated with the disease that can negatively affect female fertility:

  • Active inflammation may involve the fallopian tubes and ovaries, which can lead to infertility6. Perianal disease can further lead to dyspareunia.
  • Most medications used for IBD appear to pose greater fertility risk to men rather than women. For women, treatment with methotrexate can have negative consequences as an abortifacient and potent teratogen.
  • Surgical interventions, such as restorative protocolectomy with ileoanal anastomosis, can have  negative effects on female fertility. Two studies, evaluating the impact of proctocolectomy with pelvic pouch or end ileostomy on pelvic anatomy, showed that 50 percent of females had complete unilateral or bilateral obstruction of the fallopian tubes7,8. While various methods have been identified to prevent post-surgical adhesions in the pelvis, no data yet exists regarding their efficacy in improving fertility9. High use of fertility treatments following surgeries like ileal pouch-anal anastomosis (IPAA) further illustrates fertility difficulties faced by women with IBD after surgery. In one study that followed women after IPAA, 29% of pregnancies were carried out via IVF, compared with 1% of the general population23. At this time, there are no established guidelines for preservation of fertility in women with IBD undergoing surgery8.
Conception and Pregnancy Outcomes Disease activity at the time of conception is found to influence the course of pregnancy for women with IBD. Data shows that women with UC are more likely to have disease activity during pregnancy than women with CD, which may be a reflection of cytokine production of the placenta and subsequent impact on UC24,25. Most significantly, patients who conceive when disease is in remission are expected to experience a normal course of pregnancy. In contrast, those who conceive at time of active disease are much more likely to face continued symptoms throughout pregnancy, with up to 70% experiencing relapse and/or further deterioration26. Thus, conception at a time of remission is most advised. Pregnant women with IBD further have increased risk for antepartum hemorrhage, low birth weight infants, and premature deliveries; however, risk of congenital abnormalities do not appear to be increased12. Cesarean delivery is advised for women with history of IPAA or with active perianal disease at time of delivery6.

Table 2 describes profiles for various IBD medications used during pregnancy and breastfeeding to maintain remission9.
Effect on Male Fertility

Like women, men with IBD in remission do not appear to have decreased fertility compared with the general population30. However, fertility and sexual function in these patients are similarly affected by psychological factors, disease activity, medications, and a history of IBD-related surgery. Depression, for example, is one psychological factor that can affect patients with IBD, and use of antidepressants and anti-anxiety medications may subsequently lead to erectile dysfunction. Additional adverse effects of IBD treatment on sexual function and male fertility are as follows:

  • Men with more severe disease activity and inflammation are found to have higher rates of erectile dysfunction31.
  • Many medications have been reported to impair semen parameters. Methotrexate and sulfasalazine can cause reversible non-dose dependent oligospermia. Sulfasalazine is also associated with reduced sperm motility and abnormal sperm morphology with infertility reported in up to 60% of men33,34. Men on sulfasalazine should therefore be transitioned to 5-ASAs at least four months prior to conceiving, as fertility is shown to be restored after stopping medication or switching to other mesalazine preparations35,36. Long term therapy with cyclosporine, azathioprine, and prednisone has demonstrated no effects on fertility37; thus, there is no routine recommendation to discontinue treatments unless the patient or couple demonstrate unexplained infertility or miscarriage. Methotrexate is also most commonly associated with impotence38. Active metabolites of methotrexate remain in cell or tissues for several months after discontinuation; thus, recommendation for men with IBD is to discontinue use of methotrexate at least 3-4 months prior to attempting conception39. Anti-tumor necrosis factor agents may impair male fertility as well. Villiger et al27 demonstrated pronounced sperm abnormalities in patients with active spondyloarthritis, who were taking TNF antagonists. As it is unknown at this time whether fetal exposure to anti-TNF alpha through semen is dangerous, men with IBD and on this regimen are advised to use barrier methods throughout pregnancy9.
  • Studies on surgical history, including proctocolectomy with IPAA, have been associated with sexual dysfunction in men. In one Dutch study40, these rates were estimated up to 25% in 35 men who underwent IPAA due to UC, though 90% of these patients were ultimately satisfied with the procedure.
  • It should also be noted that there are a few reports of antisperm antibodies detected in both men and women with IBD, which could potentially contribute to decreased fertility, though little is still known. One theory is that these antibodies may result from heightened immunological response to gut microbiota antigens introduced by increased intestinal permeability, that share common antigenecity with spermatozoa41.

Table 3 reviews male side effect profiles for different IBD medications9.

References

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About the Author

Melody Besharati is a medical student at the University of California, Irvine. Inspired to be a physician after working with her research mentor in the field of adolescent oncology, Ms. Besharati carries a passion for patient advocacy. In medical school, she created treatment and wellbeing summaries for cancer patients and has written educational text for patients to empower them during interactions with their healthcare providers. Her research interests include improving young adult community access to important quality of life resources, including fertility preservation. She is currently working with Dr. Teresa Woodruff on a related study, which culminated from a research rotation at Northwestern University. Ms. Besharati has applied for the 2014-2015 Residency Match, in the field of Obstetrics and Gynecology.

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